The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein.

ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). EGFR and ERBB2 are oncoproteins and validated targets for therapeutic intervention in a variety of solid tumors. In contrast, the role that ERBB4 plays in human malignancies is ambiguous. Thus, here we review the literature regarding ERBB4 function in human malignancies. We review the mechanisms of ERBB4 signaling with an emphasis on mechanisms of signaling specificity. In the context of this signaling specificity, we discuss the hypothesis that ERBB4 appears to function as a tumor suppressor protein and as an oncoprotein. Next, we review the literature that describes the role of ERBB4 in tumors of the bladder, liver, prostate, brain, colon, stomach, lung, bone, ovary, thyroid, hematopoietic tissues, pancreas, breast, skin, head, and neck. Whenever possible, we discuss the possibility that ERBB4 mutants function as biomarkers in these tumors. Finally, we discuss the potential roles of ERBB4 mutants in the staging of human tumors and how ERBB4 function may dictate the treatment of human tumors. SIGNIFICANCE STATEMENT: This articles reviews ERBB4 function in the context of the mechanistic model that ERBB4 homodimers function as tumor suppressors, whereas ERBB4-EGFR or ERBB4-ERBB2 heterodimers act as oncogenes. Thus, this review serves as a mechanistic framework for clinicians and scientists to consider the role of ERBB4 and ERBB4 mutants in staging and treating human tumors.

[Management of emergency department inflows during the COVID-19 outbreak in the CHU of Liege : efficiency of an advanced triage center]. / Gestion des admissions aux Urgences durant la pandémie de COVID-19 au sein du CHU de Liège : Apport d'un centre de tri avancé.

In March 2020, the COVID-19 pandemic started to spread among the Belgian territory. Our university hospital was confronted to the very need of specific reorganizations guided by the implementation of the Hospital Emergency Plan.This article aims to describe the experience of the University Hospital of Liège (CHU Liège) during the COVID-19 outbreak and demonstrates the efficiency of advanced triage centers to regulate hospital admissions from the emergency department (ED). METHODS: since the beginning of March 2020, the CHU of Liège has implemented specific advanced triage centers to manage patients with SARS-CoV-2 suspected symptoms. The first center was organized inside the hospital but the need of outside structures led to the creation of two centers by the end of March. From March 2 to May 3, data from the different visits at the COVID-19 centers were collected (numbers of admissions, rationale for coming, work up and outcome). RESULTS: during the study period, 3,094 patients were admitted to the specific COVID-19 centers of the CHU Liège. This represents 3,431 visits among which 337 were classified as readmission visits. The sensitivity and specificity of the triage centers to determine the need for hospitalization were, respectively, estimated at 87,9 % and 93,4 %. CONCLUSION: our experience tends to demonstrate the role of specific COVID-19 triage centers located very close to the EDs aimed at managing COVID-19 suspected patients in order to actually determine their need for subsequent hospitalization.

La pandémie de COVID-19 a débuté au mois de mars 2020 sur le territoire belge. Elle a contraint nos institutions hospitalières à une série de réorganisations singulières soutenues par l'activation du Plan d'Urgence Hospitalier. Cet article a pour objet de décrire l'expérience du Centre Hospitalier Universitaire de Liège (CHU de Liège) durant la pandémie de COVID-19 et de relater l'efficience de la mise en place d'un centre de tri avancé en amont des services d'urgences pour la gestion des admissions hospitalières. Méthodes : dès le 2 Mars 2020, le CHU de Liège a mis en place une infrastructure d'accueil des patients suspects d'infection par le SARS-CoV-2. D'abord initiée au sein de l'institution hospitalière, la nécessité d'une infrastructure indépendante s'est rapidement révélée indispensable et a, dès lors, vu le jour dès la fin du mois de mars, sur les deux sites hospitaliers universitaires. Du 2 mars au 3 mai 2020, l'ensemble des données relatives aux visites au sein des centres de tri avancé ont été collectées (nombre d'admissions, motif des visites, examens complémentaires et évolutions cliniques). Résultats : sur la période de l'étude, 3.094 patients ont transité par les centres de tri du CHU de Liège. Cette fréquentation était constituée d'un volume global de 3.431 contacts dont 337 représentaient des réadmissions. La sensibilité et la spécificité des centres de tri en regard de la nécessité d'une hospitalisation étaient, respectivement, de 87,9 % et 93,4 %. Conclusion : notre expérience suggère une efficience optimale des centres de tri avancé, en amont des structures hospitalières traditionnelles, pour orienter de manière appropriée le flux des patients suspects d'infection par le SARS-CoV-2.

Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and ß-catenin-dependent TCF transcriptional activity.

The cyclic nucleotide phosphodiesterase 10A (PDE10) has been mostly studied as a therapeutic target for certain psychiatric and neurological conditions, although a potential role in tumorigenesis has not been reported. Here we show that PDE10 is elevated in human colon tumor cell lines compared with normal colonocytes, as well as in colon tumors from human clinical specimens and intestinal tumors from Apc(Min/+) mice compared with normal intestinal mucosa, respectively. An isozyme and tumor-selective role of PDE10 were evident by the ability of small-molecule inhibitors and small interfering RNA knockdown to suppress colon tumor cell growth with reduced sensitivity of normal colonocytes. Stable knockdown of PDE10 by short hairpin RNA also inhibits colony formation and increases doubling time of colon tumor cells. PDE10 inhibition selectively activates cGMP/cGMP-dependent protein kinase signaling to suppress ß-catenin levels and T-cell factor (TCF) transcriptional activity in colon tumor cells. Conversely, ectopic expression of PDE10 in normal and precancerous colonocytes increases proliferation and activates TCF transcriptional activity. These observations suggest a novel role of PDE10 in colon tumorigenesis and that inhibitors may be useful for the treatment or prevention of colorectal cancer.

[Blue baby syndrome: the source of the truth]. / Le cas clinique du mois. Syndrome du bébé bleu: la vérité cachée au fond du puits.

Methemoglobinemia is a rare disorder preferentially affecting children. The outcome may be dramatic when the disorder remains unidentified, however early recognition using unspecific exams allows prompt therapy. We report the case of a 14-month-old baby who presented with a sudden access of cyanosis resulting from acute methemoglobinemia. Careful investigation identified contamination of familial food by an excess of nitrates related to the use of well water from rural location.

Ossification of styloid ligament and its clinical implication a report of human casses

A case of ossification of the right styloid ligament in an adult human caucasian skull was verified duringroutine activities of the Laboratory of Human Anatomy at the University of Santa Cruz do Sul - Brazil. Thisstudy presents its clinical considerations and applications. The presence of other anatomical variations was notverified.

Exercise behavior among female occupational health nurses. Influence of self efficacy, perceived health control, and age.

Physical fitness of the American worker is a core element of personal good health and a key factor in corporate cost containment. The Centers for Disease Control and Prevention specifically notes that health professionals should be physically active not only to benefit their own health but also to make more credible their endorsement of an active lifestyle. Guided by Pender's Health Promotion Model, this study gives a profile of the current status of exercise behaviors, physical self efficacy, and perceived health control among a sample of occupational health nurses. Surveys were mailed to a random sample of 300 female members from a midwestern state association of the American Association of Occupational Health Nurses. The mean exercise score was 30.7 MET hours per week, with walking the activity most often selected. Physical self efficacy was a significant positive predictor of exercise practice, while age exerted a significant inverse effect on exercise. The study findings may be used to stimulate discussion among occupational health nurses about how their own physical self efficacy and perceived health control may influence their exercise behaviors, and how in turn these beliefs and exercise practices may influence their decisions about promoting exercise programs at their workplaces.

Use of molecular beacons to detect an antifolate resistance-associated mutation in Plasmodium falciparum.

A PCR-based technique using new fluorescent probes, called molecular beacons, was developed to detect the antifolate resistance-associated S108N point mutation in Plasmodium falciparum. One hundred African clinical isolates were tested by the new method in comparison with the PCR-restriction fragment length polymorphism method. This new molecular technique appears to be a promising tool for epidemiological studies.

Use of the Parasight-F diagnostic test for imported malaria in a travel clinic.

The Parasight-F test based on the detection of a soluble antigen specific for Plasmodium falciparum is designed for the immediate diagnosis of malaria infection. We evaluated its use by clinicians during consultations. This prospective study of its diagnostic utility in febrile patients consulting a travel clinic on their return from areas endemic for malaria was conducted between May 1996 and May 1997. The Parasight-F test was performed by the clinician with confirmation by means of standard microscopic examination of venous blood. One-hundred and forty patients were enrolled. Forty-three (31%) cases of malaria were identified by microscopic examination. Thirty-eight were due to P. falciparum. The Parasight-F tests yielded 6 false-positive and 3 false-negative results compared to the microscopic findings. The specificity and sensitivity for the diagnosis of P. falciparum malaria were 94% and 92%. These results show that the Parasight-F test alone cannot replace microscopic diagnosis of malaria in travel clinics.

Increased incidence of cycloguanil resistance in malaria cases entering France from Africa, determined as point mutations in the parasites' dihydrofolate-reductase genes.

The incidence of cycloguanil resistance in 501 Plasmodium falciparum isolates from individuals entering France from Africa was estimated by a method based on PCR-restriction-fragment-length polymorphisms. None of the subjects had taken antifol prophylaxis. Annual incidence of the resistance, detected as a point mutation at codon 108 in the parasite's dihydrofolate-reductase gene, increased from 19.8% in 1995 to 43.6% in 1997 (P < 0.001). The proportion of isolates found to be susceptible (i.e. wild-type) among travellers returning from the African countries known as Group 2 in France (i.e. Burkina Faso, Côte d'Ivoire, Gambia, Ghana, Guinea, Liberia, Madagascar, Mali, Mauritania, Niger, Senegal, Sierra Leone, Tchad and Togo) was reasonably high (62.9%) and much higher than in the other subjects returning from other identifiable countries in Africa (35.3%). The antimalarial prophylaxis recommended in France to those travelling to Group-2 countries, chloroquine-proguanil, therefore still seems reasonable, although cycloguanil resistance may seriously undermine the efficacy of this drug combination in the future.

Analysis of kappa and omega repeats of the cg2 gene and chloroquine susceptibility in isolates of Plasmodium falciparum from sub-Saharan Africa.

The correlation between the structure of two short sequences from the Plasmodium falciparum cg2 gene and parasite chloroquine susceptibility was evaluated in unselected clinical isolates obtained from travellers returning mainly from Africa to France in 1995 and 1996. As determined by an isotopic semi-microtest, 74 isolates were susceptible to chloroquine (50% inhibitory concentration < 80 nM), 13 were intermediate (80 nM < 50% inhibitory concentration < 110 nM) and 53 were resistant (50% inhibitory concentration > 110 nM). Two polymerase chain reaction assays were developed, one for the kappa and one for the omega repeat domains of cg2 gene. The kappa and the omega repeat domains of 99 isolates were sequenced. A variation in the unit number of kappa and omega repeats was observed. Variations in repetitive sequences, which were not previously described, were found: three for the kappa repeat region: kappa9; kappa10 and kappa11 and three for the omega repeat region: omega8; omega9 and omega22. A polymorphism was observed inside the repeat units of kappa and omega regions. There were six possible kappa repeat units and seven possible omega repeat units. The presence of a particular pattern, containing kappa14 and omega16 repeat units, was associated with a lack of chloroquine susceptibility in 44 out of 46 cases. However, not all resistant isolates had this 'resistant' genotype. Among 43 resistant isolates, 36 (84%) had the kappa14 repeats sequence and 36 had the omega16 repeats sequence. These results lend further support to linkage between cg2 polymorphisms and chloroquine resistance without excluding the existence of other resistance component(s).

[Considering disparities in resistance of Plasmodium falciparum in Africa in chemoprevention decisions]. / Prise en compte des disparités de résistance de Plasmodium falciparum en Afrique dans la décision chimioprophylactique.

OBJECTIVES: Assess the efficacy of preventive and curative treatments of imported malaria. METHODS: The in vitro drug susceptibility of mefloquine, chloroquine and cycloguanil was determined against African isolates of Plasmodium falciparum from imported malaria cases by an isotopic in vitro test or a genomic approach. RESULTS: Plasmodium falciparum resistance to mefloquine, chloroquine or to the dihydrofolate reductase inhibitor was present in 5.2%, 46% and 42% of isolates respectively. Plasmodium falciparum drug resistance to chloroquine or antifolinics was more frequent in permanent than in seasonal malarial transmission areas. Simultaneous resistance to chloroquine and antifolinics was observed in 17% of isolates between 1991 and 1994 and in 28% between 1995 and 1997.

Reasons for dissatisfaction: a survey of relatives of intensive care patients who died.

OBJECTIVE: To describe the reasons for eventual dissatisfaction among the families of patients who died in the intensive care unit (ICU), regarding both the assistance offered during the patient's stay in the hospital and the information received from the medical staff. DESIGN: Cross-sectional descriptive study, which was conducted after a survey using a questionnaire. SETTING: Interdisciplinary ICU (n = 8 beds) at San Giovanni Hospital in Bellinzona (CH). SUBJECTS: Three-hundred ninety families of patients who died in the ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A postal questionnaire (n = 43 questions) was sent to the families of 390 patients who died in the ICU during 8 yrs (1981 to 1989). The results referred to 123 replies: a) 82.6% of the respondents expressed no criticism of the patient's hospital stay; b) 90% considered the patient's treatment was adequate; c) 17% felt that the information received concerning diagnosis was insufficient or unclear; and d) 30% (particularly close relatives and those relatives who were informed of the death by telephone and not in person) expressed dissatisfaction regarding the information received on the cause of death. CONCLUSIONS: Our survey found that the relatives of patients who died were most dissatisfied with the care received according to: a) the type of death (e.g., sudden death vs. death preceded by a gradual deterioration in the patient's condition); and b) the manner in which the relatives were notified of the death (in person vs. by telephone). The personal characteristics of the people interviewed, such as gender and the closeness of their relationship to the deceased, also seem to have some bearing on the opinions expressed. A high percentage of respondents were satisfied with the treatment received by their dying relative and the information conveyed by caregivers. Nevertheless, the dissatisfaction expressed by some respondents indicates a need for improvement, especially in communicating information to the relatives of these patients.

[Resistance to chloroquine and cycloguanil of Plasmodium falciparum in patients arriving in France after travel in Africa without chemoprophylaxis]. / Résistance à la chloroquine et au cycloguanil de Plasmodium falciparum chez des patients arrivant en France après un voyage en Afrique sans chimioprophylaxie.

The in vitro susceptibility of chloroquine and the genomic profile of dihydrofolate reductase (DHFR) codon 108 was determined against african isolates of P. falciparum (Pf) from imported malaria cases without previous drug intake by an isotopic microtest or PCR + RFLP. Pf resistance to chloroquine or to the DHFR inhibitor was present in 49% and 46% of isolates, respectively. Pf drug resistance was more frequent in permanent than in seasonal malarial transmission areas and chloroquine plus DHFR resistance reached 28% in years 1995-97. Updating the guidelines for the prevention of malaria in travellers to Africa is necessary.

Long-term morbidity and management strategies of tracheal aspiration in adults with severe developmental disabilities.

The feeding skills and health of 73 adults with severe developmental disabilities who aspirated were examined between 1986 and 1990. Sixty individuals had profound mental retardation (82%) and 48, cerebral palsy (66%). Modified barium swallow studies, esophagrams and gastric follow-throughs were completed on 67 clients (92%). Twenty adults aspirated barium. Aspiration was specific for barium texture in 8 (40%). Mobility, level of mental retardation, or feeding skills did not discriminate those who aspirated. Mealtime respiratory distress (65%) or chronic lung disease (55%), however, were significantly associated with aspiration. More studies are needed on the early identification and management of aspiration.

["Soft" parameters and invisible resuscitation]. / I parametri soft e la rianimazione invisibile.

Caring for a patient implies performing technical interventions and caring for the whole person, recognising his/her personal life, habits, family, wills. The working experience of an intensive care unit of Bellinzona is described: the theoretical framework that led the health team to start this new approach to intensive care patients and its translation in everyday practice. Verbal and non verbal communication skills (with the patient and the team) are pivotal in this approach; relatives are considered partners in the care of the patient and an essential element of the caring environment. Nurses identified meaningful data (soft data) related to living experience of the patient, to the interaction with the healing environment, his/her patterns of communication, and their use in the intensive care unit is described.

[The inducers of stress in a hospital department]. / Induttori di stress in un ente ospedaliero.

The stress level of general medical ward (18), intensive care (15) and emergency department nurses (13) was measured with a questionnaire. For 13 intensive care and 3 emergency department nurses stress level was measured also with a computerized system (COMES). Main sources of stress among nursing personnel are death and dying, and workload. There are no differences between full time and part time nurses and apparently intensive care and emergency department nurses do not experience more stress than general medical ward nurses.

[Post-traumatic coma and pre-traumatic memory]. / Le coma post-traumatique et la mémoire pré-traumatique.

Instead of thinking that it is impossible to enter in the internal world of a comatose patient, we are now put before a new and encouraging prospective, that of the possibility, even though minimal, of influencing the vital residual organisation of the patient and to induce him perhaps to accept again external stimulations, which previously were too intense. As loss of conscience often causes loss of memory, our intention was to examine the problem of memory loss in comatose patients after accidents. The analysis of 50 questionnaires distributed to trauma-patients awakening from a comatose state and interviews give clear indications that: 1) the patients remember absolutely nothing during the time of the coma; 2) in the majority of cases (34) the patients remember in the moment preceding the accident a clear autodestructive tendency especially if they were the cause of the accident; and 3) almost all patients (41) agree to have benefited greatly from the trauma itself and from its memory.